恶性肿瘤严重威胁着人类健康。组蛋白去乙酰化酶（HDAC）已成为肿瘤治疗的重要靶点。然而，非选择性HDAC抑制剂在带来显著疗效的同时，却也带来了明显的剂量依赖毒副作用。研究表明选择性抑制HDAC6可以在保证抗肿瘤效果的同时，有效地减少或避免毒副作用的发生，开发选择性HDAC6抑制剂已成为抗肿瘤靶点的研究热点之一。前期研究发现苯乙烯异羟肟酸类化合物C1对HDAC6可以实现选择性抑制，IC50为38 nM，可以浓度依赖的上调HDAC6的生物标志物底物α-tubulin的乙酰化水平。本项目拟基于此，设计、合成化合物C1的系列新型类似物，通过构-效关系和作用机制研究发现先导化合物，再结合药理药代研究，以期获得高选择性HDAC6抑制剂候选分子应用于抗肿瘤研究。

Cancer severely affect the health of human beings. Recent studies indicated that the histone deacetylase (HDAC) could play key role in the therapy of cancer. Even though the lunched HDAC drugs have a very significant effect, but these nonselective or partially selective HDAC inhitors usually lead to undesirable biological responses dose-dependently. Studies have shown that selective HDAC6 inhibitors can reduce or avoid the toxicity. So selective inhibition of HDAC6 has been a potential and important drug target for the treatment of cancer. In our previous study, styrenated hydroxamic acid derivative compound C1 showed selectively inhibition of HDAC6 (IC50 = 38 nM), which could upregulate the aceylation level of α-tubulin (a known substrate for HDAC6). In this study, we will design and synthesis novel C1-related analogues. By analyzing the structure-activity relationship and studing the interaction between proteins and molecules to find the drug lead. Then to evaluate lead`s pharmacological activities and accomplish studies of pharmacokinetics and preliminary toxicity. In summary, these researches are aim to find a highly selective HDAC6 inhibitor with lower IC50 as drug candidate for the treatment of cancer.